The effective treatment of cancer remains a top priority for the medical establishment. Great strides have been made in the effective therapy of some systemically disseminated forms involving the blood tissues, for instance, childhood leukemia and Hodgkin's disease. However, progress in treating the most prevalent forms of solid malignant masses, of, for instance, the lung, colon, rectum and breast, as well as other less prevalent but aggressive forms, such as primary brain tumors, melanomas and the like, has been slow. This is so despite a major effort by the medical community wherein multitudinous therapeutic protocols using surgical excision, radiation therapy, chemotherapy and immunotherapy, either as individual modalities or in various combinations, have been tested in experimental models and/or clinically.
One major problem with drug therapy which has heretofore remained unresolved is one of selectivity, in other words, attainment of effective treatment of the tumor without causing damage to healthy surrounding tissues or organs. There are two general methods heretofore known by which to achieve this end: a) using an agent which is selectively toxic to the tumor, or b) selectively delivering a toxic agent to the tumor. Unlike penicillin or other antibiotics that selectively kill bacteria without damaging normal human tissues, the search for a cancer treatment "magic bullet" has remained elusive. Immunotherapy approaches using monoclonal antibodies, cytotoxic immune cells and/or other biologic response modifiers hold promise in this regard, but have thus far also demonstrated host toxicities as well as a variety of other problems
The usefulness of chemotherapeutic agents delivered systemically is severely limited due to the small amount of drug reaching the tumor and such host toxicities as myelosuppression or gastrointestinal toxicity and a variety of organ specific toxicities, such as, cardiotoxicity with adriamycin, kidney toxicity with cis-platinum and lung toxicity with bleomycin. These complications restrict both the total dosage and the number of treatments patients can tolerate. Moreover, certain therapeutic agents exhibit relatively short effective lives in the presence of body fluids and often reach the tumor in a partially or entirely deactivated condition when introduced systemically.
Regional delivery has been tested as a method of increasing the ratio of therapeutic agent delivered to the tumor versus that delivered to systemic sites of toxicity. Methods have included intra-arterial injection into arteries serving the area of the tumor, as exemplified by such techniques as liver perfusion, intraperitoneal delivery by injection or implanted delivery devices for tumors in the peritoneal cavity, delivery into cerebrospinal fluid by injection or implantable device for central nervous system tumors, intra-cavitary delivery by injection or implantable device following surgical resection and delivery by devices implanted near the tumor. These methods have also met with only limited success.
Direct intratumoral delivery offers promise, as an optimal method for delivering large quantities of antineoplastic agents to solid tumor masses while minimizing delivery to the systemic sites of toxicity. Direct intratumoral delivery has been tested on many tumor types. A wide variety of antineoplastic agents including chemotherapeutics, biotherapeutics and radiotherapeutics have been used. For example, Livraghi and co-workers, Tumori 72 (1986), pp. 81-87 have studied the effect of direct intratumoral chemotherapy in humans under ultrasound guidance. They administered standard aqueous formulations of 5-fluorouracil, methotrexate and cyclophosphamide. Tator and co-workers, Cancer Research 27 (1977), pp. 476-481 studied the effect of stereotactic intratumoral injection of two nitrosoureas, i.e., 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), and 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea (Me-CCNU) in a mouse ependymoblastoma model. These investigators tested various vehicles which might allow them to treat the tumor with very large drug doses. In their most suitable formulation these water insoluble nitrosoureas were suspended in 0.4% aqueous methylcellulose. Their experiments, sometimes using a series of up to ten separate,.temporally spaced, injections into a single tumor mass produced only modest increases in life span.
The most significant problem limiting these and other direct intratumoral therapy methods resides in the inability to deliver lethal levels of antineoplastic substance throughout the entire tumor mass. Stability and bioavailability of cytotoxic substances in the delivery vehicles has also been a problem.
In view of the above, the limitations to the treatment of cancer known to the prior art are readily apparent